Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Dendrite Morphogenesis and Plasticity Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2023 Jan 31;42(1):112028. doi: 10.1016/j.celrep.2023.112028. Epub 2023 Jan 23.
Translocon clogging at the endoplasmic reticulum (ER) as a result of translation stalling triggers ribosome UFMylation, activating translocation-associated quality control (TAQC) to degrade clogged substrates. How cells sense ribosome UFMylation to initiate TAQC is unclear. We conduct a genome-wide CRISPR-Cas9 screen to identify an uncharacterized membrane protein named SAYSD1 that facilitates TAQC. SAYSD1 associates with the Sec61 translocon and also recognizes both ribosome and UFM1 directly, engaging a stalled nascent chain to ensure its transport via the TRAPP complex to lysosomes for degradation. Like UFM1 deficiency, SAYSD1 depletion causes the accumulation of translocation-stalled proteins at the ER and triggers ER stress. Importantly, disrupting UFM1- and SAYSD1-dependent TAQC in Drosophila leads to intracellular accumulation of translocation-stalled collagens, defective collagen deposition, abnormal basement membranes, and reduced stress tolerance. Thus, SAYSD1 acts as a UFM1 sensor that collaborates with ribosome UFMylation at the site of clogged translocon, safeguarding ER homeostasis during animal development.
内质网（ER）中翻译停滞导致易位体堵塞，从而引发核糖体 UFMylation，激活易位相关质量控制（TAQC）以降解堵塞的底物。细胞如何感知核糖体 UFMylation 以启动 TAQC 尚不清楚。我们进行了全基因组 CRISPR-Cas9 筛选，以鉴定一种名为 SAYSD1 的未被表征的膜蛋白，该蛋白促进 TAQC。SAYSD1 与 Sec61 易位体结合，并且直接识别核糖体和 UFM1，与停滞的新生链结合，以确保其通过 TRAPP 复合物转运到溶酶体进行降解。与 UFM1 缺乏一样，SAYSD1 耗竭导致易位停滞蛋白在 ER 中的积累，并引发 ER 应激。重要的是，在果蝇中破坏 UFM1 和 SAYSD1 依赖性 TAQC 会导致易位停滞胶原的细胞内积累、胶原沉积缺陷、异常基底膜和应激耐受性降低。因此，SAYSD1 作为一种 UFM1 传感器，与核糖体 UFMylation 在堵塞的易位体部位协同作用，在动物发育过程中维持 ER 稳态。
